ABSTRACT: MITOCHONDRIAL GENOMICS AND METABOLISM (MGM) CORE During the previous funding cycle the Mitochondrial Genomics and Metabolism (MGM) Core assisted investigators interested in the genetics and function of mitochondria in Alzheimer's disease and aging. Our mission was to provide investigators with tools to conduct genomic, transcriptomic, proteomic, and metabolomic analyses of mitochondria, and to relate such measures to mitochondrial bioenergetics in aging and AD. Our goals were to provide cybrid cell lines to investigators exploring the hypothesis that AD is a systemic disease that affects metabolism in mitochondria derived from platelets, to genotype APOE and TOMM40 for all ADC Clinical Cohort subjects, to perform mtDNA haplotype analyses and sequence mtDNA from Clinical Cohort subjects, and to advise and assist scientists studying mitochondrial genomics or metabolism in AD and aging. An additional goal was to generate unique datasets and provide those datasets to KU ADC and outside investigators. The MGM Core accomplished each of these goals. During the next period the MGM Core will provide state of the art tools to investigators that will allow them to study mitochondrial genetics and metabolism and develop possible biomarkers for AD. We will facilitate or provide: (1) New cybrid lines derived from platelet mitochondria from 15 amyloid positive and 15 amyloid negative cognitively normal (CN) individuals (CDR=0) that are also studied by the Clinical and Neuroimaging Cores, and new cybrid lines with modified APOE genotypes. These cybrids will help investigators explore differences between amyloid positive and amyloid negative CN adults, and explore the relationship between APOE isoforms and mitochondrial function. (2) Information on mtDNA mutations associated with AD by performing next generation sequencing (NGS) on the complete Clinical Cohort. We will document the validity of mutations through duplex mtDNA sequencing, and compare brain and blood mtDNA NGS to generate data that enables correlations of disease diagnoses or endophenotypic characteristics with mtDNA mutations or heteroplasmy. (3) Development of potential AD biomarkers by characterizing epigenomic modifications of DNA bases in AD, MCI, and CN, and information on post-translational modifications of mitochondrial proteins in AD, MCI, and CN subjects from the Clinical Cohort group. (4) Assistance in methodology development for the study of mitochondrial genomics and metabolism in AD and aging, and arrange seminars or workshops focused on mitochondrial genetics, metabolism, and neurodegeneration. Through its efforts the MGM Core will assist ADC and other investigators in making new discoveries. Our involvement in pioneering studies such as the deep sequencing of mtDNA, those planned in DNA epigenomics, and the quantification and characterization of post-translational modifications of mitochondrial proteins will lead to new AD-relevant discoveries and hypotheses.